Toward Predicting Impact of Common Genetic Variants on Schizophrenia Clinical Responses With Antipsychotics: A Quantitative System Pharmacology Study

CNS disorders are lagging behind other indications in implementing genotype-dependent treatment algorithms for personalized medicine. This report uses a biophysically realistic computer model of an associative and dorsal motor cortico-striatal-thalamo-cortical loop and a working memory cortical model to investigate the pharmacodynamic effects of COMTVal158Met rs4680, 5-HTTLPR rs 25531 s/L and D2DRTaq1A1 genotypes on the clinical response of 7 antipsychotics. The effect of the genotypes on dopamine and serotonin dynamics and the level of target exposure for the drugs was calibrated from PET displacement studies. The simulations suggest strong gene-gene pharmacodynamic interactions unique to each antipsychotic. For PANSS Total, the D2DRTaq1 allele has the biggest impact, followed by the 5-HTTLPR rs25531. The A2A2 genotype improved efficacy for all drugs, with a more complex outcome for the 5-HTTLPR rs25531 genotype. Maximal range in PANSS Total for all 27 individual combinations is 3 (aripiprazole) to 5 points (clozapine). The 5-HTTLPR L/L with aripiprazole and risperidone and the D2DRTaq1A2A2 allele with haloperidol, clozapine and quetiapine reduce the motor side-effects with opposite effects for the s/s genotype. The COMT genotype has a limited effect on antipsychotic effect and EPS. For cognition, the COMT MM 5-HTTLPR L/L genotype combination has the best performance for all antipsychotics, except clozapine. Maximal difference is 25% of the total dynamic range in a 2-back working memory task. Aripiprazole is the medication that is best suited for the largest number of genotype combinations (10) followed by Clozapine and risperidone (6), haloperidol and olanzapine (3) and quetiapine and paliperidone for one genotype. In principle, the platform could identify the best antipsychotic treatment balancing efficacy and side-effects for a specific individual genotype. Once the predictions of this platform are validated in a clinical setting the platform has potential to support rational personalized treatment guidance in clinical practice.

Do oral contraceptives affect young women’s memory? Dopamine-dependent working memory is influenced by COMT genotype, but not time of pill ingestion

Background Despite the widespread use of oral contraceptives (OCs), and the well-documented influence of estrogens, notably 17β-estradiol (E2), on cognition, research relating OCs to working memory is limited and mixed. Two factors may contribute to these mixed findings: 1) pharmacokinetics of oral contraceptives, which drive fluctuations in synthetic hormone levels; and 2) genetic polymorphisms related to dopamine degradation and working memory, which interact with E2. This research investigated whether the pharmacokinetics of oral contraceptives, in concert with the single nucleotide polymorphism (Val158Met; rs4680) of the catechol-o-methyltransferase gene (COMT), influence working memory performance. Methods University-age women taking and not taking OCs were tested for working memory and genotyped for COMT. If they were not taking OCs (n = 62), sessions occurred in the early follicular (low E2) and late follicular (high E2) phase. If they were taking OCs (n = 52), sessions occurred 1–2 hours after (high ethinyl estradiol, EE) and ~24 hours after (low EE) pill ingestion. Working memory was tested using the N-back, AX-CPT, Digit Span, and Digit Ordering Tasks. Data were analyzed using multilevel models with estrogen condition, COMT, and group as predictors, controlling for mood and practice effects. Results For women taking OCs, time of pill ingestion did not influence performance. However, the subgroup with COMT val/val (low dopamine) were less accurate on 2-back lure trials than those with COMT met/met (high dopamine). For women not taking OCs, cycle phase moderated COMT’s influence on lure accuracy. When compared, women taking OCs had higher AX-CPT proactive control indices than those not taking OCs. Conclusion These findings suggest that oral contraceptives are not detrimental for young women’s working memory and that they may increase proactive control. The more pronounced effects of COMT in women taking OCs suggests that, in women taking OCs, suppressed endogenous E2–not fluctuating EE levels–may be more relevant for working memory. Future studies are needed to differentiate effects of endogenous versus synthetic estrogens on working memory.

The Effect of Green Tea Extract on Individual Components of Metabolic Syndrome in Women Who Are Post-menopause

Objectives Green tea intake may have a role in weight management and glucose control. Given the rise in prevalence of metabolic syndrome (MetS) among aging women, research regarding green tea's effect on MetS is warranted. This study aimed to determine whether green tea extract (GTE) supplementation improves components of MetS among women who are post-menopause. Methods This study was a secondary analysis of the Minnesota Green Tea Trial (MGTT), a double-blinded randomized controlled trial. Participants were a subset of the MGTT who had MetS at baseline. Participants were instructed to take four GTE capsules containing a mean (SD) 843 (44) mg epigallocatechin gallate (EGCG) or placebo daily for 12 months. Waist circumference, HDL-cholesterol, triglyceride, fasting blood glucose, diastolic and systolic blood pressure levels were measured at baseline and month 12, and changes were compared and stratified by catechol-O-methyltransferase enzyme (COMT) genotype, BMI, and the number of antihypertensive medications. One-way and two-way ANCOVA tests adjusting for age and BMI at baseline were also used for comparisons of the endpoints between treatment groups and for exploratory analyses. Results The GTE group (n = 49) experienced a significant reduction in HDL-cholesterol concentrations compared to an increase in the placebo group (n = 63) (GTE: −0.45 ± 1.27 mg/dL, Placebo: 2.95 ± 0.77 mg/dL, P = 0.04). Those in the GTE group with high-activity COMT genotype had a significant reduction in SBP compared to placebo. (Low/intermediate-activity COMT genotype GTE: −0.79 ± 2.08 mmHg, Placebo: −3.26 ± 1.67 mmHg; High-activity COMT genotype GTE: −5.64 ± 2.73 mmHg, Placebo: 1.58 ± 3.00 mmHg, P-interaction = 0.048). Those in the GTE group who took three antihypertensive medications had a significant reduction in waist circumference compared to placebo (GTE: −7.91 ± 3.72cm, placebo: 3.50 ± 2.64 cm, P-interaction = 0.04). No significant changes were found for the other endpoints. Conclusions GTE supplementation for 12 months was not associated with improvements in individual components of MetS in this population. GTE supplementation may help reduce SBP among women with high-activity COMT genotype and waist circumference in those who take three antihypertensive medications. Funding Sources NIH/National Cancer Institute.

Aberrant Brain Signal Variability and COMT Genotype in Chronic TMD Patients

The analysis of brain signal variability is a promising approach to understand pathological brain function related to chronic pain. This study investigates whether blood-oxygen-level–dependent signal variability (BOLDSV) in specific frequency bands is altered in temporomandibular disorder (TMD) and correlated to its clinical features. Twelve patients with chronic myofascial TMD and 24 healthy controls (HCs) underwent resting-state functional magnetic resonance imaging. The BOLDSV was measured as the standard deviation of the BOLD time series at each voxel and compared between groups. We also examined the potential relationship between the BOLDSV and the catechol- O-methyltransferase ( COMT) Val158Met polymorphism. We assessed sensory-discriminative pain in the craniofacial region, pain sensitivity to sustained masseteric pain challenge, and TMD pain frequency for clinical correlation. Patients displayed reduced BOLDSV in the dorsolateral prefrontal cortex (dlPFC) as compared with HC in all frequency bands. In the slow-3 band, patients also showed reduced BOLDSV in the medial dorsal thalamus, primary motor cortex (M1), and primary somatosensory cortex (S1) and heightened BOLDSV in the temporal pole. Notably, we found a significant correlation between lower BOLDSV (slow-3) in the orofacial M1/S1 regions and higher clinical pain (intensity/area) and higher sensitivity of the masseter muscle pain. Moreover, lower BOLDSV (slow-3) in the dlPFC and ventrolateral PFC was associated with a higher TMD pain frequency. Participants who had the COMT 158Met substitution exhibited lower BOLDSV in the dlPFC and higher BOLDSV in the temporal pole as compared with participants without the COMT 158Met substitution. An increasing number of Met alleles was associated with lower dlPFC and greater temporal pole BOLDSV in both HC and TMD groups. Together, we demonstrated that chronic TMD patients exhibit aberrant BOLDSV in the top-down pain modulatory and sensorimotor circuits associated with their pain frequency and severity. COMT Val158Met polymorphism might affect clinical symptoms in association with regional brain signal variability, specifically involved in cognitive and emotional regulation of pain.

Dimensions of Craving Interact with COMT Genotype to Predict Relapse in Individuals with Alcohol Use Disorder Six Months after Treatment

(1) Background: Alcohol use disorder (AUD) is associated with poor medical, psychological, and psychosocial outcomes and approximately 60% of individuals with AUD relapse six months after treatment. Craving is a core aspect of AUD and associated with high risk of relapse. One promising avenue to improve outcomes may be in understanding the relationship between COMT genotype, craving, and treatment outcomes. (2) Methods: To this end, we assessed craving, recent drinking history, and impulsivity in 70 individuals with AUD undergoing a standard course of treatment at a regional Veteran Affairs (VA) medical center. Saliva samples were collected to determine COMT genotype. In this prospective observational study, participants were followed for six months to determine who went on to relapse after treatment. (3) Results: Results revealed a significant interaction between craving and catechol-O-methyltransferse (COMT) genotype in predicting relapse. Post hoc exploratory analyses indicated that Met/Met homozygotes reported the highest levels of craving, and craving was associated with recent drinking history. Among Val/Val homozygotes, who had higher rates of relapse, craving was associated with impulsivity. (4) Conclusions: These associations highlight that specific profiles of psychological and biological factors may be important in understanding which individuals are at highest risk of relapse following treatment. Future studies that build on these findings are warranted.

First Demonstration of Double Dissociation between COMT-Met158 and COMT-Val158 Cognitive Performance When Stressed and When Calmer

We present here the first evidence of the much-predicted double dissociation between the effect of stress on cognitive skills [executive functions (EFs)] dependent on prefrontal cortex (PFC) by catechol-O-methyltransferase (COMT) genotype. The COMT gene polymorphism with methionine (Met) at codon 158 results in more dopamine (DA) in PFC and generally better EFs, while with valine (Val) at codon 158 the result is less PFC DA and generally poorer EFs. Many have predicted that mild stress, by raising PFC DA levels should aid EFs of COMT-Vals (bringing their PFC DA levels up, closer to optimal) and impair EFs of COMT-Mets (raising their PFC DA levels past optimal). We tested 140 men and women in a within-subject crossover design using extremely mild social evaluative stress. On trials requiring EFs (incongruent trials) of the Flanker/Reverse Flanker task, COMT-Val158 homozygotes performed better when mildly stressed than when calmer, while COMT-Met158 carriers performed worse when mildly stressed. Two other teams previously tried to obtain this, but only found stress impairing EFs of COMT-Mets, not improving EFs of COMT-Vals. Perhaps we found both because we used a much milder stressor. Evidently, the bandwidth for stress having a facilitative effect on EFs is exceedingly narrow.

Association between the COMT Val158Met polymorphism and antipsychotic efficacy in schizophrenia: an updated meta-analysis

Background: Catechol-O-methyltransferase (COMT) contributes to the control of synaptic dopamine (DA) transmission by catalyzing DA degradation in the presynaptic space. The COMT Val158Met polymorphism (rs4680) substantially alters enzymatic activity and consequently synaptic DA concentration in the prefrontal cortex and hippocampus. The COMT genotype could, therefore, exert a major influence on antipsychotic treatment response as many of these agents also target dopaminergic transmission. Objective: The present meta-analysis aimed to test a putative relationship between the COMT Val158Met polymorphism and antipsychotic response across different populations and antipsychotic types. Methods: Searches of PubMed, Web of Science, EMBASE, OVID, Google Scholar, and Baidu Scholar databases yielded 30 peer-reviewed studies published before January 2020 with a pooled total of 6291 participants. The Lipták–Stouffer Zscore method for meta-analysis was applied to combine data. The Z score was also calculated separately for Caucasian and Asian subgroups. Results: Pooled results indicated a highly significant association between COMT Val158Met and antipsychotic response (Z = 6.709, P = 9.8 × 10-12). Further, this relationship remained significant in subgroup analyses of Caucasian patients (Z = 3.180, P = 7.4 × 10-4 ) and Asian patients (Z = 4.487, P = 3.6 × 10-6 ). Conclusions: Pooled evidence supports the hypothesis that the COMT Val158Met polymorphism influences the antipsychotic response in both Caucasian and Asian schizophrenia patient populations. Prediction of antipsychotic response by patient genotyping may warrant closer consideration in randomized clinical trials of efficacy.

Population pharmacokinetics of levodopa gel infusion in Parkinson’s disease: effects of entacapone infusion and genetic polymorphism

Levodopa-entacapone-carbidopa intestinal gel (LECIG) provides continuous drug delivery through intrajejunal infusion. The aim of this study was to characterize the population pharmacokinetics of levodopa following LECIG and levodopa-carbidopa intestinal gel (LCIG) infusion to investigate suitable translation of dose from LCIG to LECIG treatment, and the impact of common variations in the dopa-decarboxylase (DDC) and catechol-O-methyltransferase (COMT) genes on levodopa pharmacokinetics. A non-linear mixed-effects model of levodopa pharmacokinetics was developed using plasma concentration data from a double-blind, cross-over study of LCIG compared with LECIG in patients with advanced Parkinson’s disease (n = 11). All patients were genotyped for rs4680 (polymorphism of the COMT gene), rs921451 and rs3837091 (polymorphisms of the DDC gene). The final model was a one compartment model with a high fixed absorption rate constant, and a first order elimination, with estimated apparent clearances (CL/F), of 27.9 L/h/70 kg for LCIG versus 17.5 L/h/70 kg for LECIG, and apparent volume of distribution of 74.4 L/70 kg. Our results thus suggest that the continuous maintenance dose of LECIG, on a population level, should be decreased by approximately 35%, to achieve similar drug exposure as with LCIG. An effect from entacapone was identified on all individuals, regardless of COMT rs4680 genotype. The individuals with higher DDC and COMT enzyme activity showed tendencies towards higher levodopa CL/F. The simultaneous administration of entacapone to LCIG administration results in a 36.5% lower apparent levodopa clearance, and there is a need for lower continuous maintenance doses, regardless of patients’ COMT genotype.